Study of 1,3,5-triazine-based catalytic amide-forming reactions: Effect of solvents and basicity of reactants

Article abstract of DOI:10.1248/cpb.c13-00368

Effect of the basic property of reactants (tertiary amine catalysts, a substrate amine, and acid neutralizers) on catalytic dehydrocondensation between a carboxylic acid and an amine by using 2-chloro-4,6- dimethoxy-1,3,5-triazine (CDMT) was studied. The

Full text of DOI:10.1248/cpb.c13-00368

8
82
Note
Chem. Pharm. Bull. 61(8) 882–886 (2013)
Vol. 61, No. 8
Study of 1,3,5-Triazine-Based Catalytic Amide-Forming Reactions:
Effect of Solvents and Basicity of Reactants
,
a,b
a
a
c
Munetaka Kunishima,* Masanori Kitamura, Hiroyuki Tanaka, Ichiro Nakakura,
c
b,c
Takahiro Moriya, and Kazuhito Hioki
a
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences,
b
Kanazawa University; Kakuma-machi, Kanazawa 920–1192, Japan: Cooperative Research Center of Life Sciences,
Kobe Gakuin University; and Faculty of Pharmaceutical Sciences, Kobe Gakuin University; 1–1–3 Minatojima,
c
Chuo-ku, Kobe 655–8586, Japan.
Received May 13, 2013; accepted May 31, 2013
Effect of the basic property of reactants (tertiary amine catalysts, a substrate amine, and acid neutral-
izers) on catalytic dehydrocondensation between a carboxylic acid and an amine by using 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT) was studied. The reaction yield was affected by the acid–base equilibrium
among reactants. In dichloromethane, a representative aprotic solvent, a strongly basic catalyst gave amides
in higher yields than weakly basic catalysts, regardless of the basicity of the acid neutralizer, which is called
the proton capture agent (PCA). In contrast, in protic solvents, such as methanol or aqueous methanol,
weakly basic catalysts gave amides in somewhat better yields than the strongly basic catalysts. In general,
PCAs with weakly basic properties are favorable, because those with strongly basic properties tend to give
byproducts arising from the reaction between CDMT and the substrate amine.
Key words amide; dehydrocondensation; 1,3,5-triazine; catalytic reaction; solvent effect
Dehydrocondensation to form amides and esters is an es- have not investigated the effect of the basicity of tert-amines
sential tool for organic and medicinal chemists, and various in a similar steric environment. In addition, because all the
dehydrocondensing reagents have been developed for the past reactants (carboxylates, amines, and tert-amines) can exist in
1,2)
several decades.
Among them, 4-(4,6-dimethoxy-1,3,5- an acid–base equilibrium with each other, the reaction can be
triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, Fig. affected by solvent properties. Here, we report the effects of
1
), has proven to be useful because of its stability, reactivities, the basicity of tert-amines and PCAs on the catalytic dehy-
3
–5)
and low synthetic cost.
In particular, it selectively produces drocondensations for the preparation of amides in protic and
amides from carboxylic acids and amines even in alcoholic aprotic solvents.
6
–8)
or aqueous media.
Related triazine-based compounds,
N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N,N,N-trialkylammonium Results and Discussion
chloride (DMT-Ams), which consist of tertiary amines (tert-
Effect of tert-Amine Catalysts and PCAs on the Cata-
amine) instead of N-methylmorpholine (NMM), have a similar lytic Amide-Forming Reaction in Dichloromethane To
9
–12)
reactivity for dehydrocondensation.
examine the effect of catalysts and PCAs on the catalytic
We found catalytic dehydrocondensation involving the in amide-forming reaction, we chose 2-phenylpropionic acid
situ generation of DMT-Am from a stoichiometric amount of (1a) and 2-phenethylamine (2a) as model reactants, both of
2
-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a catalytic which possess a primary aliphatic substituent and allow their
13)
amount of a tert-amine, as summarized in Chart 1. In this detection by UV absorption of the phenyl group. Since we
14)
system, the addition of a base, proton capture agent (PCA),
which is inert toward CDMT, is essential for the regeneration (Chart 1), we determined yields of the resulting amine-substi-
of the tert-amine from its hydrochloride.
tuted product (4a) in addition to the desired amide (3a). On
From this understanding, we have developed catalytic de- the basis of the reactivity of tert-amines toward CDMT caused
hydrocondensing reactions using a tert-amine with a specific by the gauche β-alkyl group, we employed NMM, N,N-
functional property, such as molecular recognition.
were concerned with the side reaction between 2a and CDMT
12)
13,15–19)
As dimethylglycine ethyl ester (DMGE), and N,N-dimethylbutyl-
functionalized catalysts, we employed an N,N-dimethylglycine amine (Me NBu) as catalysts, and triethylamine (Et N), N,N-
2
3
ester as a catalytic tert-amine part because of its facile in- diisopropylethylamine (i-Pr NEt), N-cyclohexylmorpholine
2
troduction into functional molecules via the ester group and (NCHM), N,N-diethylaniline (PhNEt ), and sodium bicarbon-
2
also because of its potent catalytic activity in a protic solvent. ate (NaHCO ) as PCAs. DMGE and Me NBu would be suit-
3
2
However, the details of the choice of catalytic tert-amine parts able catalysts for investigation of the effect of their basicity,
depending on the reaction conditions have not been described. because they have different basicities and have similar steric
Very recently, we have studied the structure–reactivity
relationship of tert-amines reacting with CDMT for the gen-
eration of DMT-Am, and proposed the gauche β-alkyl group
12)
effect. This effect indicates that a steric environment around
the nitrogen atom rather than the basicity of the tert-amines
is predominantly correlated with their reactivity. However, we
The authors declare no conflict of interest.
Fig. 1. Structure of DMT-MM and DMT-Am
*
To whom correspondence should be addressed. e-mail: kunisima@p.kanazawa-u.ac.jp
© 2013 The Pharmaceutical Society of Japan

August 2013
883
Chart 1. Catalytic Amide-Forming Reaction Involving DMT-Am
2
0)
environments around the nitrogen atom. We confirmed that 4a competes with the production of DMT-Am because of the
the tert-amines moiety of PCAs cannot serve as a catalyst be- lower nucleophilicities of these catalysts. Hydrogen chloride
cause of two or more unavoidable β-gauche alkyl groups (see, arising from the reaction of CDMT with either 2a or tert-
Supplemental Table S2).
amines followed by 1a should be captured by unreacted 2a
Table 1 shows the influence of the basicity of the catalysts or PCA rather than DMGE and NMM. The use of NaHCO3,
2
0–23)
and PCAs
on the distribution of the products (3a, 4a) in PhNEt , or NCHM, whose basicities are sufficiently lower
2
2
6)
dichloromethane (CH Cl ), which was chosen as a representa- than that of 2a, primarily results in the protonation of 2a.
2
2
tive aprotic solvent because it produced the highest yield of The resulting ammonium salt is unreactive with CDMT;
a among aprotic solvents under stoichiometric conditions therefore, a lesser amount of 4a is produced (Chart 2b). When
3
(
Supplemental Table S1). Me NBu gave the highest yield of using Et N and i-Pr NEt with the basicities comparable with
2
3
2
3a and the lowest yield of 4a in the presence of every PCA that of 2a, the amount of the reactive non-protonated form of
except PhNEt . On the other hand, in the case of the NMM or 2a should increase, causing an increased yield of 4a.
2
DMGE catalyst, the yield of 4a increased with increasing the
basicity of PCAs, whereas the yield of 3a remained moderate superior to weakly basic tert-amine catalysts such as NMM
regardless of the basicity of the PCAs. and DMGE for the catalytic amide-forming reaction in aprotic
Therefore, Me NBu with stronger basicity was found to be
2
Because the precipitation of DMT-Am, which is insoluble solvents. Consequently, the catalytic amide-forming reaction
in CH Cl , was not observed during the reactions, the rate using a combination of Me NBu and NCHM proceeds in good
2
2
2
of generation of DMT-Am would be slower than that of its yields in common aprotic solvents (Table 2). The yields were
2
4)
consumption. Therefore, we believe that the key step in the comparable to those obtained under stoichiometric conditions,
catalytic amide-forming reaction is the SnAr substitution of as shown in Supplemental Table S1.
CDMT by tert-amine producing DMT-Am. Me NBu having
Catalytic Amide-Forming Reaction in Protic Solvents
2
a large pK value would have a higher nucleophilicity than We examined the catalytic amide-forming reaction in neutral
a
2
a, as we empirically know that tert-amines generally react protic solvents, such as methanol or a 50% aqueous methanol
2
5)
with CDMT faster than primary or secondary amines.
solution (Table 3). In general, the absolute methanol produced
Thus, CDMT is quickly converted into the acyloxytriazine by higher yields of 3a and lower yields of 4a, than the 50% aque-
Me NBu catalyst regardless of the basicity of the PCAs (Chart ous methanol solution. In contrast to the reaction in dichloro-
2
2
a).
methane, in an aqueous solvent, weakly basic tert-amine cata-
In the case of NMM and DMGE having lower basicities lysts such as DMGE and NMM produced higher yields of the
than Me NBu, the direct reaction of 2a toward CDMT to give amide (3a) to some extent compared with Me NBu with strong
2
2
a)
Table 1. Effect of tert-Amine Catalysts and PCAs on the Reaction between 1a and 2a in CH Cl2
2
b)
b)
b)
DMGE pK =7.2
NMM pK =7.4
Me NBu pK =10.0
a
a
2
a
PCA
3
a (%)
4a (%)
3a (%)
4a (%)
3a (%)
4a (%)
b)
NaHCO pK =6.4
69
63
76
57
63
9
8
14
23
28
76
56
68
53
63
13
21
26
32
27
76
56
91
79
82
3
2
5
5
4
3
a
b)
PhNEt pK =6.6
2
a
b)
NCHM pK =8.3
a
b)
Et N pK =10.7
3
a
b)
i-Pr NEt pK =11.4
2
a
1
a) Yields were determined by H-NMR of the mixture of 3a and 4a after PTLC. b) The pK indicates the values of their conjugated acids (refs. 20–23).
a

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Vol. 61, No. 8
Chart 2. Mechanistic Consideration for the Effect of Acid–Base Equilibrium of Reactants on the Products Distribution in CH Cl2
2
a)
Table 2. Catalytic Amide-Formation Using Me NBu and NCHM in Aprotic Solvents
2
b)
Solvent
CH Cl
AcOEt
THF
DMSO
CH CN
2
2
3
3
4
a
a
91%
5%
89%
2%
84%
8%
87%
8%
80%
6%
1
a) Yields were determined by H-NMR of the mixture of 3a and 4a after PTLC. b) The data was cited from Table 1.
a)
Table 3. Effect of tert-Amine Catalysts and PCAs on the Reaction between 1a and 2a in Aqueous and Non-aqueous Methanolic Solvents
DMGE
NMM
Me NBu
2
Solvent
MeOH
MeOH
MeOH
PCA
3
a (%)
4a (%)
3a (%)
4a (%)
3a (%)
4a (%)
NaHCO3
NCHM
81
74
55
61
60
38
2
77
59
59
72
54
35
4
9
79
52
55
50
47
26
3
8
13
19
5
14
28
Et N
22
13
15
28
15
8
22
31
3
50% aq MeOH
50% aq MeOH
50% aq MeOH
NaHCO3
NCHM
Et N
3
1
a) Yields were determined by H-NMR of the crude product after PTLC.
basicity. Again, the basicity of the PCA affected the product Therefore, the amine-substituted product 4a was produced in
yield; in particular, a lower yield of 3a and a significantly a significantly high yield (Chart 3b). In contrast, when weakly
higher yield of 4a were obtained when using Et N.
basic PCAs, such as NCHM and NaHCO , were used, 2a hav-
3
3
In protic solvents, particularly in aqueous solvents, the ing the strongest basicity among the species in the reaction
substrates (1a, 2a) should be present as salts such as the am- media should be presents in an ionized state (as the ammoni-
monium carboxylate because of the stabilization of the ionized um salt), which causes a decrease in the yield of 4a (Chart 3c).
structures by solvation (Chart 3a). The resultant ammonium
With respect to the tert-amine catalysts, NMM and DMGE
salt of 2a will be in an acid–base dissociation equilibrium should be present in a reactive non-protonated form, which
with the catalysts and PCAs, and therefore, affects the product results in the smooth formation of DMT-Am whereas Me NBu
2
distribution. When Et N, which has strong basicity, was used should be present significantly in the protonated form within
3
as the PCA, the ammonium of 2a can be significantly depro- the reaction mixture (Charts 3d,e). Owing to a smaller popu-
tonated to form the amine, which is reactive toward CDMT. lation of the reactive non-protonated species of Me NBu, a
2

August 2013
885
Chart 3. Mechanistic Consideration for the Effect of Acid–Base Equilibrium of Reactants on the Products Distribution in Aqueous Solvents
retarded formation of DMT-Am may cause a lower yield of Experimental
1
the amide. Thus, a combination of weakly basic catalysts and
General Experimental Procedures H-NMR spectra
PCAs was found to be desirable in aqueous methanol. The ob- were recorded on BRUKER DPX400 spectrometer referenced
served better results in absolute methanol, which were not af- with tetramethysilane (δ 0.00ppm) as an internal standard. IR
fected by the basicity of tert-amine catalyst, may be due to the spectra were recorded on Nicolet FT-IR AVATAR360. Low-
somewhat intermediate polarity of methanol between aprotic and high resolution mass spectra were recorded on a JEOL
and aqueous solvents.
Ltd. the Mstation JMS-700 mass spectrometer and Micromass
Zq2000 spectrometer. Melting points were determined with
a Yanagimoto melting point apparatus and are uncorrected.
Conclusion
In the catalytic amide-forming reaction using a combination pK values were determined with Metrohm 794 Basic Titrino.
a
of CDMT and a tert-amine catalyst, we have found that the Reactions were monitored by thin-layer chromatography car-
polarity of solvents and the basicity of the catalysts and PCAs ried out on 0.25mm Merck silica gel plates (60F-254). Column
affect the distribution of the products (3a, 4a). A strongly chromatography was performed with Kanto Chemical silica
basic catalyst such as Me NBu was found to be the superior gel 60N (63–210mm, spherical, neutral). Preparative thin layer
2
catalyst in aprotic solvents as compared with weakly basic chromatography (PTLC) was performed on silica gel 60F254
catalysts such as NMM and DMGE. NMM and DMGE were (Merck). Reagents and solvents were purchased from TCI,
found to be slightly better than Me NBu in protic solvents. Nacalai Tesque, Aldrich, and Wako Pure Chemical Industries,
2
Weakly basic PCAs such as NCHM or NaHCO are found to Ltd. and were used without further purification.
3
be favorable, regardless of the solvents, because they help to
General Procedure for Catalytic Amidation To a
avoid the side reaction between CDMT and substrate amine, solution (2.37mL) of phenylpropionic acid (1a, 35.6mg,
which produces undesirable 4a. In addition, controlling the 0.237mmol), phenethylamine (2a, 31.6mg, 0.261mmol), tert-
ionization state of the substrates and catalyst was essential in amine catalyst (0.047mmol) and base (0.237mmol) were
an aqueous solution. In this regard, the advantages of N,N- added CDMT (45.8mg, 0.261mmol) at ambient temperature.
dimethylglycine esters that we have utilized for tert-amine After stirring overnight, the reaction mixture was poured
catalyst in variety of catalytic amide-forming reactions in into a mixture of water and diethyl ether. The organic layer
aqueous solvents have now been well interpreted. Based on was washed with saturated sodium bicarbonate, 1m HCl, and
these findings, we are now searching for a more effective tert- brine, dried over anhydrous MgSO , filtered, and concentrated
4
amine catalysts that can be used in aqueous solvents.
in vacuo. The residue was purified by PTLC (CHCl /MeOH=
3
9
5/5) to obtain 3a and 4a mixture. The yields were deter-
1
mined by H-NMR.

8
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Vol. 61, No. 8
3
)
M., Rovero P., Błaszczyk M., Główka M. L., Papini A. M., J. Am.
Chem. Soc., 127, 16912–16920 (2005).
11) Jastrzabek K., Kolesinska B., Sabatino G., Rizzolo F., Papini A. M.,
Kaminski Z. J., Int. J. Pept. Res. Ther., 13, 229–236 (2007).
2) Kunishima M., Ujigawa T., Nagaoka Y., Kawachi C., Hioki K.,
Shiro M., Chem. Eur. J., 18, 15856–15867 (2012).
3) Kunishima M., Yoshimura K., Morigaki H., Kawamata R., Terao
N-Phenethyl-3-phenylpropanamide (3a)
Colorless
−1
crystals (CH Cl –hexane). mp 94.5–95.5°C. IR (KBr) cm :
299, 1635, 1544. H-NMR (CDCl ) δ: 2.41 (2H, t, J=7.7Hz),
.73 (2H, t, J=6.9Hz), 2.94 (2H, t, J=7.7Hz), 3.47 (2H, td,
J=6.9, 6.0Hz), 5.37 (1H, brs), 7.15–7.30 (10H, m). MS m/z:
2
2
1
3
2
3
1
+
2
53 (M ).
1
2
4a)
,4-Dimethoxy-6-(N-phenethylamino)-1,3,5-triazine
K., Tani S., J. Am. Chem. Soc., 123, 10760–10761 (2001).
Colorless crystals mp 113.5–114°C. IR (KBr) cm : 14) We named compounds utilized for proton capture as PCAs to
12)
−1
(
3
1
3
264, 3146, 3020, 2940, 2861, 1643, 1621, 1478, 1462, 1364,
107, 815. H-NMR (CDCl ) δ: 2.90 (2H, t, J=6.9Hz),
.72 (2H, q, J=6.9Hz), 3.91 (3H, s), 3.98 (3H, s), 5.49 (1H,
brs), 7.18–7.33 (5H, m). HR-MS m/z: Calcd for C H N O ;
distinguish them from other basic compounds. Although such
compounds should be called bases, we use PCA throughout the text
to avoid any confusion, because other compounds such as tertiary
amine catalysts, substrate amines, and carboxylate anions also act
as a base during the course of the reaction involving the acid–base
equilibrium.
1
3
13
16
4
2
+
+
2
60.1273 (M ), Found; 260.1269 (M ).
1
5) Kunishima M., Hioki K., Moriya T., Morita J., Ikuta T., Tani S.,
Acknowledgment This work was supported partially by
Angew. Chem. Int. Ed., 45, 1252–1255 (2006).
a Grant-in-Aid for Science Research (No. 20390007) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
16) Kunishima M., Imada H., Kikuchi K., Hioki K., Nishida J., Tani S.,
Angew. Chem. Int. Ed., 44, 7254–7257 (2005).
17) Kunishima M., Tokaji M., Matsuoka K., Nishida J., Kanamori M.,
Hioki K., Tani S., J. Am. Chem. Soc., 128, 14452–14453 (2006).
18) Kunishima M., Kikuchi K., Kawai Y., Hioki K., Angew. Chem. Int.
Ed., 51, 2080–2083 (2012).
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)
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3
)
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20) The pK values of the conjugated acids of DMGE and NCHM were
a
determined by potentiometric pH titration by the method described
in the Supplemental information. The pKa values of other com-
pounds (the catalysts and PCAs) are found in the literature (refs.
21–23).
4)
5
6
7
)
)
)
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24) Our recent NMR study also supports this fact, see: ref. 12.
25) It has not been solved why tert-amines without the gauche β-alkyl
group preferentially react with CDMT over primary amines.
9)
26) The pK of the hydrochloride of 2a is 9.83 (ref. 21).
a
10) Kamiński Z. J., Kolesińska B., Kolesińska J., Sabatino G., Chelli